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GDNF fails to exert neuroprotection in a rat {alpha}-synuclein model of Parkinson's disease.

Decressac, Mickael LU ; Ulusoy, Ayse LU ; Mattsson, Bengt LU ; Georgievska, Biljana; Romero-Ramos, Marina; Kirik, Deniz LU and Björklund, Anders LU (2011) In Brain 134(8). p.2302-2311
Abstract
The neuroprotective effect of the glial cell line-derived neurotrophic factor has been extensively studied in various toxic models of Parkinson's disease. However, it remains unclear whether this neurotrophic factor can protect against the toxicity induced by the aggregation-prone protein α-synuclein. Targeted overexpression of human wild-type α-synuclein in the nigrostriatal system, using adeno-associated viral vectors, causes a progressive degeneration of the nigral dopamine neurons and the development of axonal pathology in the striatum. In the present study, we investigated, using different paradigms of delivery, whether glial cell line-derived neurotrophic factor can protect against the neurodegenerative changes and the cellular... (More)
The neuroprotective effect of the glial cell line-derived neurotrophic factor has been extensively studied in various toxic models of Parkinson's disease. However, it remains unclear whether this neurotrophic factor can protect against the toxicity induced by the aggregation-prone protein α-synuclein. Targeted overexpression of human wild-type α-synuclein in the nigrostriatal system, using adeno-associated viral vectors, causes a progressive degeneration of the nigral dopamine neurons and the development of axonal pathology in the striatum. In the present study, we investigated, using different paradigms of delivery, whether glial cell line-derived neurotrophic factor can protect against the neurodegenerative changes and the cellular stress induced by α-synuclein. We found that viral vector-mediated delivery of glial cell line-derived neurotrophic factor into substantia nigra and/or striatum, administered 2-3 weeks before α-synuclein, was inefficient in preventing the wild-type α-synuclein-induced loss of dopamine neurons and terminals. In addition, glial cell line-derived neurotrophic factor overexpression did not ameliorate the behavioural deficit in this rat model of Parkinson's disease. Quantification of striatal α-synuclein-positive aggregates revealed that glial cell line-derived neurotrophic factor had no effect on α-synuclein aggregation. These data provide the evidence for the lack of neuroprotective effect of glial cell line-derived neurotrophic factor against the toxicity of human wild-type α-synuclein in an in vivo model of Parkinson's disease. The difference in neuroprotective efficacy of glial cell line-derived neurotrophic factor seen in our model and the commonly used neurotoxin models of Parkinson's disease, raises important issues pertinent to the interpretation of the results obtained in preclinical models of Parkinson's disease, and their relevance for the therapeutic use glial cell line-derived neurotrophic factor in patients with Parkinson's disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adeno-associated viral vector, lentiviral vector, GDNF, Parkinson's disease, alpha-synuclein
in
Brain
volume
134
issue
8
pages
2302 - 2311
publisher
Oxford University Press
external identifiers
  • wos:000294067700016
  • pmid:21712347
  • scopus:80051985178
ISSN
1460-2156
DOI
10.1093/brain/awr149
language
English
LU publication?
yes
id
a04f2935-0ed8-4656-a3c4-64f0d267e29e (old id 2007677)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21712347?dopt=Abstract
date added to LUP
2011-07-06 11:32:10
date last changed
2017-10-29 03:16:37
@article{a04f2935-0ed8-4656-a3c4-64f0d267e29e,
  abstract     = {The neuroprotective effect of the glial cell line-derived neurotrophic factor has been extensively studied in various toxic models of Parkinson's disease. However, it remains unclear whether this neurotrophic factor can protect against the toxicity induced by the aggregation-prone protein α-synuclein. Targeted overexpression of human wild-type α-synuclein in the nigrostriatal system, using adeno-associated viral vectors, causes a progressive degeneration of the nigral dopamine neurons and the development of axonal pathology in the striatum. In the present study, we investigated, using different paradigms of delivery, whether glial cell line-derived neurotrophic factor can protect against the neurodegenerative changes and the cellular stress induced by α-synuclein. We found that viral vector-mediated delivery of glial cell line-derived neurotrophic factor into substantia nigra and/or striatum, administered 2-3 weeks before α-synuclein, was inefficient in preventing the wild-type α-synuclein-induced loss of dopamine neurons and terminals. In addition, glial cell line-derived neurotrophic factor overexpression did not ameliorate the behavioural deficit in this rat model of Parkinson's disease. Quantification of striatal α-synuclein-positive aggregates revealed that glial cell line-derived neurotrophic factor had no effect on α-synuclein aggregation. These data provide the evidence for the lack of neuroprotective effect of glial cell line-derived neurotrophic factor against the toxicity of human wild-type α-synuclein in an in vivo model of Parkinson's disease. The difference in neuroprotective efficacy of glial cell line-derived neurotrophic factor seen in our model and the commonly used neurotoxin models of Parkinson's disease, raises important issues pertinent to the interpretation of the results obtained in preclinical models of Parkinson's disease, and their relevance for the therapeutic use glial cell line-derived neurotrophic factor in patients with Parkinson's disease.},
  author       = {Decressac, Mickael and Ulusoy, Ayse and Mattsson, Bengt and Georgievska, Biljana and Romero-Ramos, Marina and Kirik, Deniz and Björklund, Anders},
  issn         = {1460-2156},
  keyword      = {adeno-associated viral vector,lentiviral vector,GDNF,Parkinson's disease,alpha-synuclein},
  language     = {eng},
  number       = {8},
  pages        = {2302--2311},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {GDNF fails to exert neuroprotection in a rat {alpha}-synuclein model of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1093/brain/awr149},
  volume       = {134},
  year         = {2011},
}